Monobactam hydrazides containing catechol sulfonic acid groups

ABSTRACT

Compounds having the formula ##STR1## and pharmaceutically acceptable salts thereof, wherein R 3  and R 4  are the same or different and each is hydrogen or alkyl or R 3  and R 4  taken together with the nitrogen atoms to which they are attached form a 1,2-diazacyclobutane, 1,2-diazacyclopentane, 1,2-diazacyclohexane, or 1,2-diazacycloheptane ring and Y, and Y 2  are either hydrogen or hydroxy but are not the same; are useful chemical intermediates for the preparation of β-lactam antibiotics.

This is a division of application Ser. No. 468,412, filed Jan. 22, 1990,now U.S. Pat. No. 5,030,724.

BACKGROUND OF THE INVENTION

United Kingdom patent application No. 2071650 published Sept. 23, 1981describes monocyclic β-lactam antibiotics having a sulfonic acid saltsubstituent in the 1-position of the β-lactam nucleus and an acylaminosubstituent in the 3-position of the β-lactam nucleus.

U.S. Pat. No. 4,610,824 describes beta-lactams having the formula##STR2## wherein R₁ and R₂ are each independently hydrogen or alkyl of 1to 4 carbon atoms, or R₁ and R₂ together with the carbon atom to whichthey are attached form a cycloalkyl ring;

R₃ is hydrogen or alkyl;

R₄ is hydrogen or alkyl, and R₅ can be phenylcarbonyl or substitutedphenylcarbonyl.

BRIEF DESCRIPTION OF THE INVENTION

Compounds having the formula ##STR3## and pharmaceutically acceptablesalts thereof, have antibacterial activity. In formula I, and throughoutthe specification, the symbols are as defined below.

R₁ and R₂ are each independently hydrogen or alkyl of 1 to 4 carbonatoms, or R₁ and R₂ together with the carbon atom to which they areattached form a cycloalkyl ring;

R₃ and R₄ are the same or different and each is hydrogen or alkyl or R₃and R₄ taken together with the nitrogen atoms to which they are attachedform a 1,2-diazacyclobutane, 1,2-diazacyclopentane,1,2-diazacyclohexane, or 1,2-diazacycloheptane ring.

R₅ and R₆ are the same or different and each is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4, 5, 6 or7-membered heterocycle, or one of R₅ and R₆ is hydrogen and the other isazido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl,2-phenylethenyl, 2-phenylethynyl, carboxyl, --CH₂ X₁ [wherein X₁ isazido, amino (NH₂), hydroxy, carboxyl, alkoxycarbonyl, alkanoylamino,phenylcarbonylamino, (substituted phenyl)carbonylamino,alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy,phenyl, substituted phenyl cyano, ##STR4## --S--X₂, or --O--X₂ (whereinA, X₂, X₆ and X₇ are as hereinafter defined), --S--X₂ or --O--X₂[wherein X₂ is alkyl, substituted alkyl, phenyl, substituted phenyl,phenylalkyl, (substituted phenyl)alkyl, alkanoyl, substituted alkanoyl,phenylalkanoyl, (substituted phenyl)alkanoyl, phenylcarbonyl,(substituted phenyl)carbonyl, heteroaryl, heteroarylalkyl,heteroarylalkanoyl or heteroarylcarbonyl, and in the case of when X₁ isO--X₂ then X₂ can also be alkylideneamino, alkanoylamino,carboxyalkylideneamino, alkylsulphonylamino, alkoxycarbonyl,alkylsulphonylamino or N,N-cyclodialkanoylamino]. In addition R₅ and R₆can be ##STR5## [wherein ore of X₃ and X₄ is hydrogen and the other ishydrogen or alkyl, or X₃ and X₄ when taken together with the carbon atomto which they are attached form a cycloalkyl group; and X₅ is formyl,alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl,phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl,alkoxycarbonyl, aminocarbonyl (substituted amino)carbonyl, or cyano(--C.tbd.N)], ##STR6## [wherein A is --CH═CH--, --(CH₂)_(m) --,--(CH₂)_(m) --O--, --(CH₂)_(m) --NH--, or --CH₂ --S--CH₂ --, m is 0, 1or 2, and X₆ and X₇ are the same or different and each is hydrogen,alkyl, phenyl or substituted phenyl, or X₆ is hydrogen and X₇ is amino,substituted amino, alkanoylamino or alkoxy, or X₆ and X₇ when takentogether with the nitrogen atom to which they are attached form a 4, 5,6 or 7-membered heterocycle];

R₁₁ is hydrogen, alkanoyl of from one to ten carbon atoms, substitutedalkanoyl of from two to ten carbon atoms, phenylcarbonyl, (substitutedphenyl)carbonyl, heteroarylcarbonyl, phenylalkanoyl, (substitutedphenyl) alkanoyl, or heteroarylalkanoyl.

Y₁ and Y₂ are either hydrogen or OR₁₁ but are not the same;

Listed below are definitions of various terms used to describe theβ-lactams of this invention. These definitions apply to the terms asthey are used throughout the specification (unless they are otherwiselimited in specific instances) either individually or as part of alarger group.

The terms "alkyl" and "alkoxy" refer to both straight and branched chaingroups. Those groups having 1 to 10 carbon atoms are preferred.

The term "cycloalkyl" refers to cycloalkyl groups having 3,4,5,6 or 7carbon atoms.

The term "substituted alkyl" refers to alkyl groups substituted with oneor more (preferably 1, 2 or 3) azido, amino (--NH₂), halogen, hydroxy,carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy,phenyloxy, (substituted phenyl)oxy, R_(a) -oxy (wherein Ra is ashereinafter defined), mercapto, alkylthio, phenylthio, (substitutedphenyl)thio, alkylsulfinyl, or alkylsulfonyl groups.

The terms "alkanoyl", "alkenyl", and "alkynyl" refer to both straightand branched chain groups. Alkanoyl groups having 1 to 10 carbon atomsare preferred. Alkenyl and alkynyl groups having 2 to 10 carbon atomsare preferred.

The term "substituted alkanoyl" refers to alkanoyl groups containingmore than one carbon atom which are substituted with one or more(preferably 1, 2 or 3) azido, amino (--NH₂), halogen, hydroxy, carboxy,cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy,(substituted phenyl)oxy, mercapto, alkylthio, phenylthio, (substitutedphenyl)thio, alkylsulfinyl or alkylsulfonyl groups.

The term "substituted phenyl" refers to a phenyl group substituted with1, 2 or 3 amino (--NH₂), halogen, hydroxyl, trifluoromethyl, alkyl (of 1to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), alkanoyloxy,aminocarbonyl, or carboxy groups.

The expression "a 4, 5, 6 or 7-membered heterocycle" (referred to as"Ra") refers to substituted and unsubstituted, aromatic and non-aromaticgroups containing one or more (preferably 1, 2 or 3) nitrogen, oxygen orsulfur atoms. Exemplary substituents are oxo (═O), halogen, hydroxy,nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons, alkoxy of1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl,2-furfurylideneamino ##STR7## benzylideneamino and substituted alkylgroups (wherein the alkyl groups have 1 to 4 carbons). One type of "4,5, 6 or 7-membered heterocycle" is the "heteroaryl" group. The term"heteroaryl" refers to those 4,5,6, or 7-membered heterocycles which arearomatic. Exemplary heteroaryl groups are substituted and unsubstitutedpyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl,imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl,and tetrazolyl. Exemplary nonaromatic heterocycles (i.e., fully orpartially saturated heterocyclic groups) are substituted andunsubstituted azetidinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl,imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl,dihydrothiazolyl and hexahydroazepinyl. Exemplary of the substituted4,5-6 or 7-membered heterocycles are 1-alkyl-3-azetidinyl,2-oxo-1-imidazolidinyl, 3-alkylsulfonyl-2-oxo-1-imidazolidinyl,3-benzylideneamino-2-oxo-1-imidazolidinyl,3-alkyl-2-oxo-1-imidazolidinyl, 3-phenyl (or substitutedphenyl)-2-oxo-1-imidazolidinyl, 3-benzyl-2-oxo-1-imidazolidinyl,3-(2-aminoethyl)-2-oxo-1-imidazolidinyl, 3-amino-2-oxo-1-imidazolidinyl,3-[(alkoxycarbonyl)amino]2-oxo-1-imidazolidinyl, 3-[2-[(alkoxycarbonyl)amino]ethyl]-2-oxo-1-imidazolidinyl, 2-oxo-1-pyrrolidinyl,2-oxo-3-oxazolidinyl, 4-hydroxy-6-methyl-2-pyrimidinyl,2-oxo-1-hexahydroazepinyl, 2-oxo-3-pyrrolidinyl,2-oxo-3-tetrahydrofuranyl, 2,3-dioxo-1-piperazinyl,2,5-dioxo-1-piperazinyl, 4-alkyl-2,3-dioxo-1-piperazinyl, and4-phenyl-2,3-dioxo-1-piperazinyl.

The term "substituted amino" refers to a group having the formula --NX₈X₉ wherein X₈ is hydrogen, alkyl, phenyl, substituted phenyl,phenylalkyl or (substituted phenyl)alkyl, and X₉ is alkyl, phenyl,substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy,cyano, alkoxy, phenylalkoxy, or amino (--NH₂).

The compounds of this invention form basic salts with inorganic andorganic bases which are also within the scope of this invention. Suchsalts include ammonium salts, alkali metal salts, alkaline earth metalsalts, and salts with organic bases such as dicyclohexylamine,benzathine, N-methyl-D-glucamine, hydrabamine and the like.

The compounds of this invention are pictured as acids. They can alsoexist, however, as zwitterions (internal or inner salts), and these arealso included within the language "pharmaceutically acceptable salts"and the scope of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The β-lactams of formula I, and pharmaceutically acceptable saltsthereof, have activity against gram-positive and gram-negativeorganisms. Of particular interest is the good activity against gramnegative organisms in vitro and in vivo exhibited by the compounds ofthis invention. The compounds of this invention can be used as agents tocombat bacterial infections (including urinary tract infections andrespiratory infections) in mammalian species such as domesticatedanimals (e.g., dogs, cats, cows, horses, and the like) and humans.

For combating bacterial infections in mammals, a compound of thisinvention can be administered to a mammal in need thereof in an amountof about 1.4 mg/kg/day to about 350 mg/kg/day, preferably about 14mg/kg/day to about 100 mg/kg/day. All modes of administration which havebeen used in the past to deliver penicillins and cephalosporins to thesite of the infection are also contemplated for use with β-lactams ofthis invention. Such methods of administration include oral,intravenous, intramuscular, and as a suppository.

The compounds of this invention wherein R₁₁ is hydrogen can be preparedusing a variety of procedures. One method utilizes as a startingmaterial the known monocyclic β-lactam antibiotics having the formula##STR8## and salts thereof. Compounds of formula II are described in theliterature; see, for example, United Kingdom patent application No.2,071,650, published Sept. 23, 1981. Reaction of a compound of formulaII with a hydrazide having the formula ##STR9## or a salt thereof, inthe presence of a coupling agent, yields the desired products of formulaI. If the starting material of formula II is an inner salt (--SO₃ H inthe 1-position), it is preferable to first treat the compound with oneequivalent of a base (e.g. tributylamine or trioctylamine) to form asalt of the sulfonic acid. Preferably, the reaction is run in thepresence of a substance capable of forming a reactive intermediate insitu, such as N-hydroxybenzotriazole and a catalyst such asdimethylaminopyridine, using a coupling agent such asdicyclohexylcarbodiimide. Exemplary solvents which can be used for thereaction are dimethylformamide, tetrahydrofuran, dichloromethane ormixtures thereof.

Compounds of the formula III are novel compounds, and as such form anintegral part of this invention. When R₃ and R₄ are the same or when R₃is hydrogen and R₄ is alkyl the compounds can be prepared by reactingesters of the formula ##STR10## with hydrazines of the formula ##STR11##

The reaction proceeds best in an excess of compound V as solvent or withmethanol as cosolvent Compounds of the formula IV can be prepared byesterifying acids of the formula ##STR12##

Well-known esterification procedures can be used for the reaction.Exemplary techniques include the use of methanol and thionyl chloride,methanol and sulfuric acid, and methanol and hydrochloric acid.

The compound of formula VI wherein Y₁ is hydroxy and Y₂ is hydrogen isknown.

The compound of the formula VI wherein Y₁ is hydrogen and Y₂ is hydroxyis prepared from commercial 2,3-dihydroxybenzoic acid by well-knownsulfonation procedures such as with a mixture of sulfuric acid andsulfur trioxide.

When R₃ is alkyl and R₄ is hydrogen, compounds of the formula III can beprepared from compounds of the formula ##STR13## wherein R₇ is aprotecting group such as (1,1-dimethylethoxy)carbonyl, ortriphenylmethyl. The protecting group can be cleaved using well knownacidic reagents such as trifluoroacetic acid or formic acid, in anunreactive solvent such as dichloromethane or chloroform, in thepresence of a scavenger such as anisole or thioanisole. Compounds of theformula VII can be prepared by reacting compounds of the formula##STR14## with compounds of the formula VI, using a coupling agent suchas dicyclohexylcarbodiimide, preferably in the presence of a substancecapable of forming a reactive intermediate in situ such asN-hydroxybenzotriazole. Exemplary solvents which can be used for thereaction are dimethylformamide, tetrahydrofuran, or dichloromethane, ormixtures thereof.

Alternatively, compounds of this invention can be prepared by thereaction of compounds of formula VI with hydrazides of the formula##STR15## in the presence of a coupling agent. The compounds of formulaVI and IX are reacted in the form of the salts of their sulfonic acids.These salts are either formed with inorganic bases during thepreparation of VI and IX, or are formed when compounds of formulae VIand IX are treated with one equivalent of a base (e.g., tributylamine ortrioctylamine). Preferably the reaction is run in the presence of asubstance capable of forming a reactive intermediate in situ, such asN-hydroxybenzotriazole and a catalyst such as dimethylaminopyridine,using a coupling agent such as dicyclohexylcarbodiimide. Exemplarysolvents which can be used for the reaction are dimethylformamide,tetrahydrofuran, dichloromethane or mixtures thereof.

Compounds of the formula IX wherein R₃ and R₄ are hydrogen are describedin the literature; see, for example, U.S. Pat. No. 4,610,824. Compoundsof the formula IX wherein R₃ and R₄ are alkyl and are the same or form aring can be prepared by reacting compounds of the formula II withhydrazines of the formula V in the presence of a coupling agent such asdicyclohexylcarbodiimide. Preferably the reaction is run in the presenceof a substance capable of forming a reactive intermediate in situ, sucha N-hydroxybenzotriazole and a catalyst such as dimethylaminopyridine.Exemplary solvents which can be used for the reaction aredimethylformamide, tetrahydrofuran, dichloromethane or mixtures thereof.

Compounds of the formula IX wherein R₃ and R₄ are different can beprepared from compounds of the formula ##STR16## wherein R₈ is aprotecting group such as (1,1-dimethylethoxy)carbonyl ortriphenylmethyl. The protecting group can be cleaved using well knownacidic reagents such as trifluoroacetic acid or formic acid, in anunreactive solvent such as dichloromethane or chloroform, in thepresence of a scavenger such as anisole or thioanisole. The reaction ispreferably done with cooling to, for example, 0° C., to minimizedecomposition of the reactants.

Compounds of the formula X can be prepared by reacting compounds of theformula II with protected hydrazines of the formula ##STR17## in thepresence of a coupling agent. If the starting material of formula II isan inner salt (--SO₃ H in the 1-position), the compound is first treatedwith one equivalent of base (e.g., tributylamine or trioctylamine) toform the salt of the sulfonic acid. Preferably, the reaction is run inthe presence of a substance capable of forming a reactive intermediatein situ, such as N-hydroxybenzotriazole and a catalyst such asdimethylaminopyridine, using a coupling agent such asdicyclohexylcarbodiimide. Exemplary solvents which can be used for thereaction are dimethylformamide, tetrahydrofuran, dichloromethane ormixtures thereof.

Hydrazine derivatives of the formulae V, VIII and XI, and methods fortheir preparation, are well known in the literature. Reviews of theirsynthesis can be found in Smith, "The Chemistry of Open-Chain OrganicNitrogen Compounds", Vols. I and II, Benjamin Inc., New York, Amsterdam,1966; Muller, "Methoden der Organischen Chemie" (Houben-Weyl), Vol.10/2, Georg Theime Verlag Stuttgart, 1967; Sandler and Karo, "OrganicFunctional Group Preparations", Vol. 1, Academic Press, New York, 1968and Timberlake and Stowell, "The Chemistry of Hydrazo, Azo, and AzoxyGroups", ed. S. Patai, part 1, Interscience, New York.

Alternatively, compounds of the formula X can be prepared by reactingazetidines of the formula ##STR18## with compounds of the formula##STR19## in the presence of a coupling agent. It is preferable to firsttreat the compound of the formula XII with one equivalent of a base(e.g. tributylamine or trioctylamine) to form a salt of the sulfonicacid. Preferably, the reaction is run in the presence of a substancecapable of forming a reactive intermediate in situ, such asN-hydroxybenzotriazole and a catalyst such as dimethylaminopyridine,using a coupling agent such as dicyclohexylcarbodiimide. Exemplarysolvents which can be used for the reaction are dimethylformamide,tetrahydrofuran, dichloromethane or mixtures thereof.

Azetidines of the formula XII are well known in the literature, see forexample the United Kingdom patent application No. 2,071,650, publishedSept. 23, 1981.

Compounds of the formula XIII can be prepared by reacting compounds ofthe formula ##STR20## or a salt thereof (for example, the hydrochloridesalt) with 2-amino-4-thiazole glyoxylic acid which has the formula##STR21## Exemplary solvents for this reaction are dimethylformamide,ethanol, dioxane, water or mixtures thereof.

Compounds of the formula XIV can be prepared by reacting compounds ofthe formula ##STR22## with hydrazine or methyl hydrazine. Exemplarysolvents for this reaction are dichloromethane, tetrahydrofuran ormixtures thereof.

Compounds of the formula XVI can be prepared by reacting compounds ofthe formula XI with compounds of the formula ##STR23## where Z is ahalogen or a hydroxyl. When Z is halogen the reaction is carried out inthe presence of a base such as tributylamine or trioctylamine, in anunreactive solvent. Exemplary solvents which can be used for thisreaction are tetrahydrofuran, dichloromethane, toluene or mixturesthereof. When Z is hydroxyl, the reaction can be run in the presence ofa substance capable of forming a reactive intermediate in situ, such asN-hydroxybenzotriazole, and a catalyst such as dimethylaminopyridine,using a coupling agent such as dicyclohexylcarbodiimide. Exemplarysolvents which can be used for this reaction are dimethylformamide,tetrahydrofuran, dichloromethane, or mixtures thereof. Alternatively,when Z is hydroxyl, the carboxylic acid can be activated by forming amixed anhydride with isobutylchloroformate or ethylchloroformate in thepresence of a base such as N-methylmorpholine or tributylamine.Exemplary solvents which can be used for this reaction aredimethylformamide, tetrahydrofuran or dichloromethane or mixturesthereof.

Compounds of the formula XVII are well known in the literature, see forexample, U.S. Pat. No. 4,610,824, published Sept. 9, 1986.

Alternatively, compounds of this invention can be prepared by reactingcompounds of the formula ##STR24## wherein R₁₂ is hydrogen or a formylgroup with compounds of the formula ##STR25## or salts thereof in asolvent such as dimethylformamide, ethanol or water, or in mixturesthereof, and in the case of where R₁₂ is formyl, hydrolyzing the productin aqueous mineral acid such as hydrochloric to remove the formylprotecting group.

Compounds of the formula XVIII are described in the literature or can beprepared from compounds of the formulae XII and XV by the methodsdescribed in the literature. See for example European Patent No. 86,556,published Aug. 24, 1983.

Compounds of the formula XIX can be prepared from compounds of theformula ##STR26## wherein R₉ is a protecting group such as(1,1-dimethylethoxy)carbonyl or triphenylmethyl. The protecting groupcan be cleaved using well known acidic reagents such as trifluoroaceticacid or formic acid, in an unreactive solvent such as dichloromethane orchloroform, in the presence of a scavenger such as anisole orthioanisole.

Compounds of the formula XX can be prepared from compounds of theformula ##STR27## wherein Y₃ and Y₄ are either hydrogen or OR₁₀ but arenot the same, and R₁₀ is a hydrogenolytically labile protecting groupsuch as benzyl. The protecting group R₁₀ can be removed byhydrogenolysis with hydrogen and a catalyst such as palladium on asupport such as charcoal in a solvent such as methanol or ethanol, or inmixtures thereof.

Compounds of the formula XXI can be prepared by reacting compounds ofthe formula ##STR28## with compounds of the formula ##STR29## in thepresence of a coupling agent such as isobutylchloroformate orethylchloroformate in the presence of a base such as N-methylmorpholineor tributylamine and a catalyst such as 4-(N,N-dimethylamino)pyridine.If the starting material of the formula XXII is an inner salt, it ispreferable to first treat the compound with one equivalent of a base(e.g. tributylamine or trioctylamine) to form a salt of the sulfonicacid. The reaction is carried out in a solvent such asdimethylformamide, tetrahydrofuran, or methylene chloride, or inmixtures thereof. Alternatively, the reaction of compounds of theformula XXII with compounds of the formula XXIII can be carried out inthe presence of a coupling agent such as dicyclohexylcarbodiimide,preferably in the presence of a substance capable of forming a reactiveintermediate in situ, such as N-hydroxybenzotriazole and a catalyst suchas dimethylamino pyridine. The reaction is carried out in a solvent suchas dimethylformamide, tetrahydrofuran, or methylene chloride, or in amixture thereof.

Compounds of the formula XXII wherein R₃ and R₄ are the same or R₃ ishydrogen and R₄ is alkyl can be prepared from compounds of the formula##STR30## by reaction with compounds of the formula V in a fashionanalogous to that used in the preparation of compounds of the formulaIII from compounds of the formula IV.

Compounds of the formula XXIV are prepared by reacting compounds of theformula IV with an arylmethyl halide such as benzyl bromide in thepresence of a base such as potassium carbonate or sodium carbonate, in asolvent such as dimethylsulfoxide or dimethylformamide.

Compounds of the formula XXIII are prepared from compounds of theformula ##STR31## by hydrolysis using an inorganic base such aspotassium hydroxide in a solvent such as methanol.

Compounds of the Formula XXV can be prepared from compounds of theformula ##STR32## by standard methods of protection such as the reactionwith BOC anhydride in a solvent such as acetonitrile.

Compounds of the formula XXVI are known in the literature.

Compounds of the invention wherein R₁₁ is acyl can be prepared from thecompounds of formula I where R₁₁ is hydrogen using methods well known inthe literature. See for example "Advanced Organic Chemisty" by J. March,published by John Wiley & Sons, Inc., page 346, and references citedtherein. Examples of acylation methods include the Schotten-Baumannprocedure using acyl halides in aqueous alkali. The acylation with acylhalides can also be carried out in a suitable organic solvent such aschloroform with an organic base present as an acid scavenger, such astriethylamine. The reaction can also proceed in a base as solvent, suchas pyridine, or with a cosolvent such as toluene. Alternatively thecompounds of the formula I wherein R₁₁ is hydrogen can be solubilized inan inert solvent such as dichloromethane by conversion of the sulfonicacid to a lipophilic salt such as tetrabutylammonium, and then reactedwith acyl halide and a suitable organic base such as tributylamine ortrioctylamine.

The compounds of formula I contain at least one chiral center - thecarbon atom (in the 3-position of the β-lactam nucleus) to which theacylamino substituent is attached. This invention is directed to thoseβ-lactams which have been described above, wherein the stereochemistryat the chiral center in the 3-position of the β-lactam nucleus is thesame as the configuration at the carbon atom in the 6-position ofnaturally occurring penicillins (e.g., penicillin G) and as theconfiguration at the carbon atom in the 7-position of naturallyoccurring cephalosporins (e.g. cephalosporin C).

The compounds of formula I have the imino substituent ##STR33## and can,therefore, exist as the syn or anti isomer or as a mixture of isomers.All of these isomeric forms are within the scope of this invention. Ingeneral, however, the syn isomer of a compound of formula I has thegreatest activity.

The following examples are specific embodiments of this invention.

EXAMPLE 1[2S-[2α,3β(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)-amino]-2-oxoethylidene]amino]oxy]-2-methyl-propanoicacid, 2-(3,4-dihydroxy-5-sulfobenzoyl)hydrazide, dipotassium saltEXAMPLE 1A 3,4-Dihydroxy-5-sulfobenzoic acid, methyl ester

3,4-Dihydroxy-5-sulfobenzoic acid, monopotassium salt (10.0 g, 36.7mmoles) was slurried in 300 ml of dry methanol, cooled to 0° C., andtreated for five minutes with dry hydrogen chloride. The resultingsolution was allowed to warm to room temperature and was stirred for 48hours. The mixture was filtered and the volatile materials were removedin vacuo. The resulting solid was dried in vacuo at 60° C. to give thetitle compound, 8.51 g, m.p. 116° C.

IR (KBr) 1712cm⁻¹

¹ H-NMR(370 MHz, D₂ O): δ=4.65(s, 3H);7.40(s, 1H);7.80(s, 1H) ppm

EXAMPLE 1B 3,4-Dihydroxy-5-sulfobenzoic acid hydrazide

3,4-Dihydroxy-5-sulfobenzoic acid, methyl ester (15.0 g, 52.9 mmoles)was dissolved in 100 ml of hydrazine hydrate and refluxed for 15 hours.The mixture was then evaporated in vacuo, the residue dissolved in waterand the pH adjusted to 1.0 with 2N hydrochloric acid. The mixture waschilled at 0° C. for 15 hours and the white precipitate which formed wasfiltered and dried to give 12.83 g of the title 2 5 compound as a whitesolid, m.p >300° C.

IR (KBr): 1657cm⁻¹

¹ H-NMR(370 MHz, D₂ O/DMSO-d₆): δ=7.30(s, 1H); 7.60(s, 1H) ppm

EXAMPLE 1C[2S-[2α,3β(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid,2-(3,4-dihydroxy-5-sulfobenzoyl)hydrazide, dipotassium salt

[2S-[2α,3β(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid (130 mg, 0.31 mmoles) was slurried in 5 ml of dimethylformamide at0° C. and treated with hydroxybenzotriazole hydrate (47 mg, 0.31mmoles), tri-n-butylamine (57 mg, 0.31 mmoles) and4-(N,N-dimethylamino)pyridine (13 mg, 0.11 mmoles). A solution ofdicylohexylcarbodiimide (63 mg, 0.31 mmoles) in 2 ml ofdimethylformamide was added, the mixture stirred at 0° C. for 1 hour,and the resulting slurry treated with a solution of3,4-dihydroxy-5-sulfobenzoic acid hydrazide (76 mg, 0.31 mmoles) andtri-n-butylamine (57 mg, C.31 mmoles) in 5 ml of dimethylformamide. Thereaction pH was raised to 7.0 with the addition of tri-n-butylamine. Themixture was stirred at 20° C. for 15 hours, and was then evaporated todryness in vacuo. The residue was dissolved in acetone and treated witha solution of potassium perfluorobutanesulfonate (210 mg, 0.61 mmoles)in 2 ml of acteone. The resulting solid was filtered, washed withacetone and dried in air. The solid was chromatographed on HP 20* inwater to give 85 mg of the title compound as a solid.

IR (KBr): 1762cm⁻¹

¹ H-NMR(370 MHz, DMSO-d₆ /D₂ O): δ=1.30(d, 3H); 4.06(m, 3H); 4.78(s,6H); 5.19(d,1H); 7.01(s, 1H); 7.38(s, 1H); 7.44(s, 1H) ppm

EXAMPLE 2[2R-[2α,3α(Z,S)]]-2-[[[1-(2-Amino-4-thiazolyl)-2[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)-amino]-2-oxoethylidene]amino]oxy]propanoic acid,2-(3,4-dihydroxy-5-sulfobenzoyl)hydrazide, disodium salt

[2R-[2α,3α(Z,S)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)-amino]-2-oxoethylidene]amino]oxy]propanoic acid(420 mg, 1.0 mmole) was slurried in 15 ml of dimethylformamide at 0° C.and treated with hydroxybenzotriazole hydrate (153 mg, 1.0 mmole),tri-n-butylamine (185 mg, 1.0 mmole) and 4-(N,N-dimethylamino)pyridine(10 mg, 0.08 mmoles). A solution of dicyclohexylcarbodiimide (206 mg,1.0 mmole) in 1 ml of dimethylformamide was added, the mixture stirredat 0° C. for 1 hour, and the resulting slurry treated with a solution of3,4-dihydroxy-5-sulfobenzoic acid hydrazide (240 mg, 1.0 mmole) andtri-n-butylamine (185 mg, 1.0 mmole) in 3 ml of dimethylformamide. Thereaction pH was raised to 7.0 with the addition of tri-n-butylamine. Themixture was stirred at 20° C. for 48 hours, filtered, and then wasevaporated to dryness in vacuo. The residue was slurried in 100 ml ofwater, the solution pH raised to 6.0 with sodium bicarbonate solution,and the solution passed through a bed of ion-exchange resin (DOWEXAG-50) in the sodium form. The resulting solution was concentrated invacuo, the pH adjusted to 2.0 with 10% hydrochloric acid, andchromatographed on HP 20 in a water-acetonitrile gradient. The productresulting from lyophilization was taken up in water, the pH adjusted to6.0 with sodium bicarbonate, and chromatographed on HP20. Lyophilizationof the product fractions gave 80 mg of the title compound as a solid.

IR (KBr): 1761cm⁻¹

¹ H-NMR(370 MHz, D₂ O): δ=1.39(d, 3H); 1.52(d, 3H); 4.46(m, 1H); 4.89(q,1H); 7.06(s, 1H); 7.41(s, 1H); 7.68(s, 1H) ppm

EXAMPLE 3 3,4-Dihydroxy-5-sulfobenzoic acid,[2R-[2α,3α(Z)]]-2-[[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino-oxy]acetyl]hydrazide,disodium salt

[2R-[2α,3α(Z)]]-2-[[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]2-oxoethylidene]amino]oxy]aceticacid, (600 mg, 1.5 mmoles) was slurried in 10 ml of dimethylformamide at0° C. and treated with hydroxybenzotriazole hydrate (228 mg, 1.5mmoles), tri-n-butylamine (278 mg, 1.5 mmoles) and4-(N,N-dimethylamino)pyridine (10 mg, 0.08 mmoles). A solution ofdicyclohexylcarbodiimide (309 mg, 1.5 mmoles) in 2 ml ofdimethylformamide was added, the mixture stirred at 0° C. for 0.75h.,and the resulting slurry treated with a solution of3,4-dihydroxy-5-sulfobenzoic acid hydrazide (360 mg, 1.5 mmoles) andtri-n-butylamine (278 mg, 1.0 mmole) in 10 ml of dimethylformamide. Thereaction pH was raised to 7.0 with the addition of tri-r-butylamine. Themixture was stirred at 20° C. for 15 hours, filtered, and then wasevaporated to dryness in vacuo. The residue was slurried in water, thesolution pH raised to 6.0 with sodium bicarbonate solution, and thesolution passed through a bed of ion-exchange resin(DOWEX AG-50) in thesodium form. The resulting solution was concentrated in vacuo, the pHadjusted to 2.0 with 10% hydrochloric acid, and chromatographed on HP20in a water-acetonitrile gradient. The product resulting fromlyophilization was taken up in water, the pH adjusted to 6.0 with sodiumbicarbonate, and chromatographed on HP20. Lyophilization of the productfractions gave 110 mg of the title compound as a solid.

IR (KBr): 1758cm⁻¹

¹ H-NMR(370 MHz, D₂ O): δ=1.37(d, 3H); 4.46(m, 1H); 4.84(s, 1H); 5.33(d,1H); 7.02(s, 1H); 7.11(s, 1H); 7.68(s, 1H) ppm

EXAMPLE 4 [2R-[2α,3α(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]2-methylpropanoicacid, 2-(3,4-dihydroxy-5-sulfobenzoyl)hydrazide, disodium salt EXAMPLE4A 3,4-Dihydroxy-5-sulfobenzoic acid hydrazide, sodium salt

The compound of Example 1B (10.58 g, 42.6 mmole) was dissolved in asolution of sodium hydroxide (1.70 g, 42.4 mmole) and 100 ml of water at20° C. Chilling at 0° C. overnight, filtering, washing with cold waterand drying in vacuo gave 3.37 g of title compound, m.p. >300° C.

IR(KBr): 1665 cm⁻¹

¹ H-NMR(DMSO-d₆): δ=7.30 (d, 1H); 7.60 (d, 1H) ppm

EXAMPLE 4B[2R-[2α,3α(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, 2-(3,4-dihydroxy-5-sulfobenzoyl)hydrazide, disodium salt

[2R-[2α,3α(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, (2.61 g, 6.0 mmoles) was dissolved in 100 ml of dimethylformamideat 0° C. and treated with hydroxybenzotriazole hydrate (810 mg, 6.0mmoles), tri-n-butylamine (1.43 ml, 6.0 mmoles) and4-(N,N-dimethylamino)pyridine (20 mg, 0.16 mmoles). A solution ofdicyclohexylcarbodiimide (1.36 g, 6.6 mmoles) in 20 ml ofdimethylformamide was added, the mixture stirred at 0° C. for 1 hour,and the resulting slurry treated with a solution of3,4-dihydroxy-5-sulfobenzoic acid hydrazide, sodium salt (1.62 g, 6.0mmoles) in 50 ml of dimethylformamide. The mixture was stirred at 20° C.for 15 hours, then was filtered and evaporated to dryness in vacuo. Theresidue was dissolved in 100 ml of acetone, the solution filtered, andthe filtrate treated with potassium perfluorobutanesulfonate (2.23g, 6.6mmoles). The resulting slurry was stirred for 1 hour at 20° C. and thesolid was filtered. The solid was dissolved in water (30 ml) andconverted to the sodium salt by passing through an ion-exchange resin(DOWEX AG-50, sodium form). The solution was concentrated andchromatographed on HP20 in water to give 1.30 g of the title compound asa solid.

IR (KBr): 1760cm⁻¹

¹ H-NMR(200 MHz, DMSO-d₆ +TFA): δ=1.28(d, 3H); 1.49(s, 3H); 1.50(s, 3H);4.10(m, 1H); 4.18(m, 1H); 7.15(s, 1H); 7.33(d, 1H) 7.65(d, 1H) ppm

EXAMPLE 5 [2R-[2α,3α(Z)]]-2-[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]2-methylpropanoicacid, 2-(2,3-dihydroxy-5-sulfobenzoyl)hydrazide, monopotassium saltEXAMPLE 5A 2,3-Dihydroxy-5-sulfobenzoic acid dipotassium salt

2,3-Dihydroxybenzoic acid (15.4g, 0.1 moles) was dissolved in smallportions at 5° C. in 80 ml of sulfuric acid containing 30% sulfurtrioxide. The mixture was allowed to warm to 20° C. over 1 h and wasthen poured slowly into 1L of vigorously stirred ice water. The pH wasadjusted to 4.5 with 30% potassium hydroxide and the solid formed wasremoved by filtration. The filtrate was diluted with a 1.5 fold volumeof methanol and filtered again. This filtrate was evaporated to 200 mland the pH was adjusted to 6.0 with potassium hydroxide. Acetone (500ml) was added and the resulting white precipitate was filtered and driedto give 18 g of crude product. Chromatography of this solid on HP20 inwater gave 12.8 g of pure title compound after lyophilization.

IR (KBr): 1700cm⁻¹

¹ H-NMR(DMSO-d₆): d =7.00(d, 1H); 7.55(d, 1H) ppm

EXAMPLE 5B 2,3-Dihydroxy-5-sulfobenzoic acid, methyl ester monopotassiumsalt

2,3-Dihydroxy-5-sulfobenzoic acid, dipotassium salt (6.2 g, 20 mmole)was dissolved in 200 ml of methanol, chilled to 0° C., and treated with100 ml of thionyl chloride dropwise. The solution was allowed to warm to20° C. then was refluxed for 20 hours. The mixture was evaporated invacuo and the solid residue was dissolved in water (15 ml). The pH wasadjusted to 4.5 with potassium hydroxide solution and the mixturechromatographed on HP20 in water. Lyophilization of the productfractions gave 4.0 g of the title compound as a solid.

IR (KBr): 1680cm⁻¹

¹ H-NMR(DMSO-d₆): d =3.90(s, 3H); 7.30(d, 1H) 7.55(d, 1H) ppm

EXAMPLE 5C 2,3-Dihydroxy-5-sulfobenzoic acid hydrazide

2,3-Dihydroxy-5-sulfobenzoic acid, methyl ester, monopotassium salt (2.7g, 9.4 mmole) and neat hydrazine (0.88 ml, 28 mmoles) in 100 ml ofmethanol were refluxed for 48 hours. The resulting white precipitate wasfiltered, dried, and dissolved in water (10 ml). Acidification to pH=2.5 with 2N hydrochloric acid, filtering and drying gave 940 mg of thetitle compound as a solid.

IR (KBr): 1675cm⁻¹

¹ H-NMR(DMSO-d₆ +TFA-d): d =7.35(d, 1H); 7.55(d, 1H) ppm

EXAMPLE 5D 2R-[2α,3α(Z)]]-2-[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, 2-(2,3-dihydroxy-5-sulfobenzoyl)hydrazide, monopotassium salt

2R-[2α,3α(Z)]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid (868 mg, 2mmole) and tri-n-butylamine (370 mg, 2 mmole) in 30 ml ofdimethylformamide at 0° C. were treated with N-hydroxybenzotriazolemonohydrate (306 mg, 2 mmole) and dicyclohexylcarbodiimide (500 mg, 2.4mmole). The mixture was stirred at 0° C. for 1 hour and at 20° C. for 6hours, and the resulting solid was removed by filtration. A secondsolution was prepared by dissolving 2,3-dihydroxy-5-sulfobenzoic acidhydrazide (490 mg, 2 mmole) and tri-n-butylaylamine (0.52 ml, 2.2 mmole)in 20 ml of dimethylformamide at 20° C. and filtering after 1 hour. Thesecond solution was added to the first and the mixture was stirred for15 hours at 20° C. before evaporating to dryness in vacuo. The residuewas dissolved in acetone and was treated with a solution of potassiumperfluorobutanesulfonate (750 mg, 2.2 mmole) in acetone at 0° C. Theresulting precipitate was collected and purified on HP20, eluting withwater. The product fractions were lyophilized, taken up in water, andthe pH adjusted to 2.0 with 2N hydrochloric acid. Chromatography on HP20and lyophilization of the product fractions gave 55 mg of the titlecompounds as a solid.

IR (KBr): 1760cm⁻¹

¹ H-NMR(200 MHz, DMSO-d₆ +TFA): δ=1.27(s, 3H); 1.50(s, 6H); 4.10(m, 1H);5.18(m, 1H); 7.12(s, 1H); 7.25(d, 1H); 7.72(d, 1H) ppm

EXAMPLE 6[2R-[2α,3α(Z,S)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]propanoicacid, 2-(2,3-dihydroxy-5-sulfobenzoyl)hydrazide, disodium salt EXAMPLE6A 2,3-Dihydroxy-5-sulfobenzoic acid, monosodium salt

2,3-Dihydroxybenzoic acid (10.0 g, 65 mmole) was added with vigorousstirring at 20° C. to 60 ml of sulfuric acid containing 30% sulfurtrioxide. After 30 minutes at ambient temperature the mixture was cooledin ice and treated cautiously with water (40 ml) and then with 130 ml ofsaturated aqueous sodium chloride. The white solid which precipitatedwas filtered and recrystallized from water to give the title compound as12.3 g of a white solid.

IR (KBr): 1685 cm⁻¹

¹ H-NMR(DMSO-d₆ +TFA): δ=7.28 (d,1H); 7.55 (d,1H) ppm

EXAMPLE 6B 2,3-Dihydroxy-5-sulfobenzoic acid methyl ester, monosodiumsalt

2,3-Dihydroxy-5-sulfobenzoic acid, monosodium salt (100 g, 0.39 mole)was added to 1.5L of dry methanol. The mixture was chilled at 0° C.while hydrogen chloride gas was introduced for 30 minutes. The mixturewas refluxed overnight then was evaporated to dryness. The residue wastaken up again in 1.5 L of dry methanol and the procedure repeated, withrefluxing for 48 hours. The mixture was filtered hot and evaporated to1.3 of its volume and cooled, whereupon the title compound crystallized.Filtration gave 93 g of a white solid.

¹ H-NMR(DMSO-d₆): δ=3.92(s, 3H); 7.89 (d, 1H); 7.65 (d, 1H) ppm

EXAMPLE 6C 2,3-Dihydroxy-5-sulfobenzoic acid hydrazide, monosodium salt

2,3-Dihydroxy-5-sulfobenzoic acid, methyl ester, monosodium salt (30.0g, 0.11 mole) was dissolved partially in 800 ml of boiling methanol andthe mixture treated at reflux dropwise with anhydrous hydrazine (6.9 ml,0.22 mole). After refluxing for 15 hours, the mixture was cooled and theprecipitated solid was filtered and dried to give 21.7 g of the titlecompound.

IR (KBr): 1642cm⁻¹

¹ H-NMR(DMSO-d₆): δ=6.75(d); 7.45(d) ppm

[2R-[2α,3α(Z,S)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]propanoicacid, 2-(2,3-dihydroxy-5-sulfobenzoyl)hydrazide, disodium salt

[2R-[2α,3α(Z,S)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)-amino]-2-oxoethylidene]amino]oxy]propanoicacid, monopotassium salt (1.68 g, 4.0 mmole) was dissolved in 60 ml ofdimethylformamide and treated at 0° C. with tributylamine (0.82 ml, 4.0mmole), N-hydroxybenzotriazole hydrate (0.62 g, 4.0 mmole),dicyclohexylcarbodiimide (0.99 g, 4.8 mmole), and4-(N,N-dimethylamino)pyridine (20 mg). The mixture was stirred at 0° C.for 1 hour, then at 20° C. for 6 hours. The slurry was filtered and thefiltrate treated with a slurry of 2,3-dihydroxy-5-sulfobenzoic acidhydrazide, monosodium salt (1.08 g, 4.0 mmole) and tri-n-butylamine(0.89 ml, 4.4 mmole) in 10 ml of dimethylformamide. The resultingmixture was stirred at 20° C. overnight, then was evaporated in vacuo.The residue was triturated with 50 ml of dry acetone to give a colorlesssolid. This solid was dissolved in water and passed over an ion-exchangeresin (DOWEX 50-Wx8, Na+ form). The eluent was lyophilized and theresulting solid was chromatographed on Organogen* in water to give thetitle compound as 183 mg of a white lyophilate.

IR (KBr): 1755cm⁻¹ β-lactam carbonyl

¹ H-NMR(DMSO-d₆ +TFA-d): δ=1.25(d, 3H); 1.40(d, 3H); 4.10(m, 1H);4.95(q, 1H); 5.15(q, 1H); 7.10(s, 1H); 7.10(s, 1H) 7.25(d, 1H); 7.70(d,1H) ppm

EXAMPLE 7 2,3-Dihydroxy-5-sulfobenzoic acid,[2R-[2α,3α(Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]acetyl]hydrazide, disodium salt EXAMPLE 7A[(1,1-Dimethylethoxy)carbonyl]aminooxyacetic acid, methyl ester

A solution of aminooxyacetic acid, methyl ester (79.3 g, 0.75 mole) andBOC anhydride (197 g, 0.9 mole) in 320 ml of acetonitrile was heated at80° C. for 24 hours. The solvent was evaporated in vacuo and the oilyresidue was partitioned between ethyl acetate and water. Drying of theorganic phase over sodium sulfate and evaporation gave 137 g of thetitle compound as a colorless oil.

IR (film): 1690-1770 cm¹

¹ H-NMR(DMSO-d₆): δ=1.30(s, 9H); 3.55(s, 3H); 4.25(s, 2H); 10.05(s, 1H)ppm

EXAMPLE 7B [(1,1-Dimethylethoxy)carbonyl]aminooxyacetic acid

[(1,1-Dimethylethoxy)carbonyl]aminooxyacetic acid, methyl ester (18.0 g,0.087 mole) and potassium hydroxide (7.4 g, 0.13 mole) were stirred in60 ml of methanol for one hour at ambient temperatures. The mixture wasneutralized with concentrated hydrochloric acid and evaporated todryness in vacuo. The residue was taken up in 100 ml of water andacidified to pH 2.5. Extraction with ethyl acetate, drying overmagnesium sulfate and evaporation gave the title compound as 6.8 g of acolorless solid, m.p. 95°-98° C.

IR (KBr): 1720, 1750 cm⁻¹

¹ H-NMR(DMSO-d₆): δ=1.35(s, 9H); 4.20(s, 2H); 10.0(s, 1H) ppm

EXAMPLE 7C 2,3-Di(phenylmethoxy)-5-sulfobenzoic acid methyl ester,monopotassium salt

A slurry of anhydrous potassium carbonate (75 g, 0.54 mmole) in 200 mlof dimethyl sulfoxide was treated with the compound of Example 6b,2,3-dihydroxy-5-sulfobenzoic acid methyl ester, monosodium salt (19.0 g,70 mmole) and benzyl bromide (18.32 ml, 154 mmole). The mixture wasstirred at 50° C. for 15 hours and then was filtered. The filtrate wasevaporated in vacuo and the residual oil was partitioned between ethylacetate and water. The organic phase was dried over magnesium sulfateand evaporated. The residue was crystallized from hexane and ethylacetate and dried in vacuo to give 24 g of the title compound as acolorless solid.

IR (KBr): 1690 cm⁻¹

¹ H-NMR(DMSO-d₆): δ=3.80(s, 3H); 4.00(s, 2H); 5.20(s, 2H); 7.2-7.6(m,12H) ppm

EXAMPLE 7D 2,3-Di(phenylmethoxy)-5-sulfobenzoic acid hydrazide

2,3-Di(phenylmethoxy)-5-sulfobenzoic acid methyl ester, monopotassiumsalt (24 g, 51.44 mmole) and anhydrous hydrazine (4.08 ml, 129 mmole)were dissolved in 450 ml of methanol and the mixture was heated atreflux for 40 hours. The resulting white precipitate was filtered offand was dissolved in 250 ml of hot water. The pH was adjusted to 2whereupon a white solid separated. Filtering gave 16.8 g of thehydrazide. Another 0.6 g of product was obtained from evaporation andacidification of the methanol mother liquors, for a total yield of 17.4g.

IR(KBr): 1675 cm⁻¹

¹ H-NMR(DMSO-d₆): δ=5.05(s, 2H); 5.25(s, 2H); 6.6(s, broad); 7.30-7.70(m, 12H); 9.70(s, 1H broad) ppm

EXAMPLE 7E 2,3-Di(phenylmethoxy)-5-sulfobenzoic acid,2-[[[(1,1-dimethylethoxy)-carbonyl]aminooxy]acetyl]hydrazide

A solution of [(1,1-dimethylethoxy)carbonyl]aminooxy acetic acid(Example 7b, 1.0g, 5.2 mmole) and N-methylmorpholine (0.57 ml, 5.2mmole) in 10 ml of dimethylformamide at -10° C. was treated dropwisewith isobutylchloroformate (0.74 ml, 5.7 mmole). The mixture was stirredat -10° C. for 1 hour, then was treated with a suspension of2,3-di(phenylmethoxy)-5-sulfobenzoic acid hydrazide (2.24g, 5.2 mmole)in 20 ml of dimethylformamide followed by the dropwise addition of asolution of N-methylmorpholine (0.86 ml, 7.8 mmole) and 4-(N,N-dimethylamino)pyridine (30 mg) in 10 ml of dimethylformamide over 20minutes. The reaction was stirred for 1 hour at 0° C., then was allowedto warm to ambient temperatures overnight. Evaporation in vacuo gave anoil which was taken up in 30 ml of water. The pH was adjusted to 2 withaqueous hydrochloric acid and the oily product was extracted into ethylacetate. Drying over magnesium sulfate and evaporation gave a residuewhich crystallized with hexane. The solid was filtered and dried to give2.3g. mp 103°-105° C.

IR (KBr): 1710 cm¹

¹ H-NMR(DMSO-d₆ +TFA-d): δ=1.40(s, 9H); 4.40, 5.05 and 5.20(3×s, 2Heach); 7.2-7.6(m, 12H) ppm

EXAMPLE 7F 2,3-Dihydroxy-5-sulfobenzoic acid,2-[[[(1,1-dimethylethoxy)-carbonyl]aminooxy]acetyl]hydrazide

2,3-Dihydroxy-5-sulfobenzoic acid,[[[(1,1-dimethylethoxy)carbonyl]aminooxy]acetyl]-hydrazide (2.0 g, 3.3mmole) and 0.5 g of 10% palladium on charcoal catalyst in 40 ml ofmethanol was hydrogenated until uptake ceased. The catalyst wasfiltered, the solvent evaporated and the residue triturated with hexaneto give 1.44 g of crystals, m.p. 148°-150° C.

IR(KBR): 1650, 1700 cm¹

¹ H-NMR(DMSO-d₆ +TFA-d): δ=1.40(s, 9H); 4.40(s, 2H); 7.3(d, 1H) ppm

EXAMPLE 7G 2,3-Dihydroxy-5-sulfobenzoic acid,2-[(aminooxy)acetyl]hydrazide

A suspension of 2,3-dihydroxy-5-sulfobenzoic acid,2-[[[(1,1-dimethylethoxy)carbonyl]aminooxy]acetyl]hydrazide (1.3 g, 3.0mmole) in 10 ml of dichloromethane at -10° C. was treated dropwise with10 ml of trifluoroacetic acid. The mixture was allowed to warm to roomtemperature and was stirred for 2 hours. The mixture was diluted with 30ml of ether and filtered to give 1.2 g of a white solid.

IR (KBr): 1650, 1720 cm¹

¹ H-NMR(DMSO-d₆ +TFA-d): δ=4.65(s, 2H); 7.3 (d, 1H); 7.7 (d, 1H) ppm

2,3-Dihydroxy-5-sulfobenzoic acid,[2R-[2α,3α(Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]acetyl]hydrazide,disodium salt

A mixture of 2,3-dihydroxy-5-sulfobenzoic acid,2-[(aminooxy)acetyl]hydrazide (0.6 g, 1.9 mmole) and[2S-(2α,3α)]-3-[[(2-amino-4-thiazolyl)-oxoacetyl]-amino]-2-methyl-4-oxo-1-azetidinesulfonic acid (0.62 g, 1.9 mmole) in 25 ml ofdimethylformamide was stirred at room temperature for 15 hours (pH 2.5when spotted on wet pH paper). The mixture was then evaporated in vacuoand the residue was chromatographed on Organogen in water. Productfractions were combined, lyophilized, redissolved in water and the pHadjusted to 5.5 with 2N sodium hydroxide. Chromatography on Organogen inwater and lyophilization of the product fractions gave 89 mg of thetitle compound as a white solid, m.p. >190° C.

IR (KBr): 1760 cm⁻¹

¹ H-NMR(DMSO-d₆ +TFA-d): δ=1.23(d, 3H); 4.83(s, 2H); 5.13(d, 1H);7.10(s, 1H); 7.25(s, 1H); 7.70(s, 1H) ppm

EXAMPLE 8 2R-[2α,3α(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy-2-methylpropanoicacid, 2-(3,4-dihydroxy-5-sulfobenzoyl)-1-methylhydrazide dipotassiumsalt EXAMPLE 8A 1-[(Phenylmethoxy)carbonyl]-1-methylhydrazine

An icecold, stirred solution of methylhydrazine (36. 8 g, 0.8 mole) andtriethylamine (161.6 g, 1.6 mole) in 700 ml of tetrahydrofuran wastreated dropwise with benzylchloroformate (136.5 g, 0.8 moles). Stirringwas continued for 15 hours at 20° C. and the volatiles were removed invacuo. The residue was partitioned between ethyl acetate and water.Insoluble material was filtered and the organic phase was washed withwater, dried over magnesium sulfate, and evaporated. The resulting oilwas triturated with 1L of ethyl ether and the etherial solution decantedfrom the insoluble material and evaporated to an oil. The oil wasdissolved in a mixture of methanol (200 ml) and concentratedhydrochloric acid (25 ml) and the volatiles removed in vacuo. Theresidue was recrystallized from a mixture of ethanol and ethyl acetateto give 22 g of a colorless crystalline solid. This material wasdissolved in water and the pH adjusted to 9.0 with sodium hydroxide. Themixture was extracted with ethyl acetate and the organic phase was driedover magnesium sulfate and evaporated in vacuo to give the titlecompound as a colorless oil, 19.0 g.

¹ H-NMR(90MHz, CDCl₃): δ=3.00(s, 3H); 4.68(s, 2H); 5.12(s, 2H); 7.40(m,5H) ppm

EXAMPLE 8B1-[(1,1-Dimethylethoxy)carbonyl]-2-[(phenylmethoxy)carbonyl-2-methylhydrazine

A mixture of 1-[(phenylmethoxy)carbonyl]-1-methylhydrazine (15.80 g, 87mmole), BOC-anhydride (24.00 g, 110 mmole), and4-(N,N-dimethylamino)-pyridine (10mg) in acetonitrile (40 ml) and water(40 ml) was heated at 60° C. for 48 hours. The solvents were evaporatedand the residue was dissolved in ethyl acetate. The solution was washedwith 0.1M aqueous citric acid, dried over magnesium sulfate, andevaporated. The residue was chromatographed on silica gel in ethylacetate and cyclohexane (1:1) to give 15.0 g of the title compound as acolorless solid, m.p. 60°-65° C.

IR (Film): 1700(s); 3270(m) cm⁻¹

¹ H-NMR(100MHz, DMSO-d₆): δ1.38 (s, 9H); 3.03 (s, 3H); 5.10(s, 2H);7.35(s, 5H); 9.35 (s, 1H) ppm

EXAMPLE 8C 15 1-[(1,1-Dimethylethoxy)carbonyl]-2-methylhydrazine

A solution of1-[(1,1-dimethylethoxy)carbonyl]-2-[(phenylmethoxy)carbonyl]-2-methylhydrazine(15.0 g, 53. mmole) in 100 ml of methanol containing 4.9 ml ofconcentrated hydrochloric acid was hydrogenated at 1 atm in the presenceof 3.0 g of 10% palladium-on-charcoal catalyst for 1 hour. The catalystwas filtered and the solvents were removed in vacuo. The residue wasdissolved in water, the pH adjusted to 8.0 with sodium hydroxide and themixture was extracted with ethyl acetate. The organic phase was driedover magnesium sulfate and evaporated to give 5.6 g of the titlecompound as a colorless solid, m.p. 50° C.

IR (KBr): 760(m); 1705(s); 2980(s) cm¹

¹ H-NMR(90MHz, CDCl₃): δ=1.48(s, 9H); 2.65(s, 3H); 6.30(s, br, 1H) ppm

EXAMPLE 8D2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-oxy]-2-methylpropanoic acid,2-[(1,1-dimethylethoxy)carbonyl]-1-methylhydrazide

A solution of2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]-2-methylpropanoylchloride (5.3 g, 22 mmole) in 40 ml of dry tetrahydrofuran was treatedwith triethylamine (4.10 ml, 30 mmole) and 4-(N,N-dimethylamino)pyridine(5 mg). A solution of 1-[(1,1-dimethylethoxy)carbonyl]-2-methylhydrazine(2.90 g, 20 mmole) in 20 ml of tetrahydrofuran was added dropwise at 0°C. and the resulting mixture was stirred at 20° C. overnight. Thesolvent was evaporated and the solid residue was partitioned betweenethyl acetate and water. The organic phase was washed successively with0.5N hydrochloric acid, 5% sodium bicarbonate, and water. Drying overmagnesium sulfate and evaporation gave 6.6 g of the title compound as acolorless solid, m.p. 140°-145° C.

¹ H-NMR(DMSO-d₆): δ=1.42 and 1.49 (two singlets, 15H) ppm

EXAMPLE 8E 2-(Aminooxy)-2-methylpropanoic acid,2-[(1,1-dimethylethoxy)carbonyl]-1-methylhydrazide

A stirred solution of2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]-2-methylpropanoic acid,2-[(1,1-dimethylethoxy)carbonyl]-1-methylhydrazide (7.10 g, 19 mmole) in50 ml of dichloromethane at 0° C. was treated dropwise with hydrazinehydrate (1.80 ml, 38 mmole). After 30 minutes the resulting slurry wasfiltered and the filtrate evaporated. The residue was crystallized fromether/petroleum ether to give the title compound as 3.3 g of a colorlesssolid, m.p. 85°-90° C.

IR(KBr): 1635(s); 1735(s); 2990(s) cm⁻¹

¹ H-NMR(DMSO-d₆): δ=1.25(s, 6H); 1.42(s, 9H); 2.95(s, br, 3H); 5.83(s,br, 2H); 9.25(s, br, 1H) ppm

EXAMPLE 8F2-[[[(2-Amino-4-thiazolyl)carboxylmethylidene]-amino]oxy]-2-methylpropanoicacid, 2-[(1,1-dimethylethoxy)carbonyl]-1-methylhydrazide

A solution of 2-amino-4-thiazole glyoxylic acid (1.72 g, 10 mmole) in 25ml of dimethylformamide was treated with a solution of2-(aminooxy)-2-methylpropanoic acid,2-[1,1-dimethylethoxy)carbonyl]-1-methylhydrazide (2.47 g, 10 mmole) in10 ml of dimethylformamide. After stirring overnight at 25° C., thesolvent was evaporated in vacuo and the oily residue was crystallizedfrom ethyl ether. Filtering and drying gave 3.3 g of the title compoundas a yellow crystalline solid, m.p. 145° C.

IR (KBr): 1655(s); 1730(s) cm⁻¹

¹ H-NMR(DMSO-d₆): δ=1.42(s, 15H); 2.92(s, br, 3H); 6.75(s, 1H); 7.20(s,br, 2H) ppm

EXAMPLE 8G[2R-[2α,3α(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)-amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, 2-[(1,1-dimethylethoxy)carbonyl]-1-methylhydrazide, potassium salt

A solution of2-[[[(2-amino-4-thiazolyl)-carboxylmethylidene]amino]oxy]-2-methylpropanoicacid, 2-[(1,1-dimethylethoxy)carbonyl]-1-methylhydrazide (2.00 g,5mmole) and N-hydroxybenzotriazole monohydrate (0.76 g, 5 mmole) in 40ml of dimethylformamide at 0° C. was treated withdicyclohexylcarbodiimide (1.23 g, 6 mmole) and the mixture was stirredfor 10 minutes. A solution of[2R-(2α,3α)]-3-amino-2-methyl-4-oxo-1-sulfoazetidine (0.83 g, 5 mmole)and triethylamine (0.70 ml, 5 mmole) in 20 ml of dimethylformamide wasadded dropwise at 0° C. The resulting mixture was stirred and allowed towarm to room temperature overnight. The mixture was filtered and thefiltrate was evaporated in vacuo. The residue was dissolved in acetone,filtered, and the filtrate treated with potassiumperfluorobutanesulfonate (1.90 g, 5.5 mmole). Ether was added and theprecipitated solid was filtered. Chromatography on Organogen with awater-acetonitrile gradient gave the title compound, 1.40 g, as a whitelyophilate.

IR (KBr): 1765(s) cm⁻¹ β-lactam carbonyl

¹ H-NMR(DMSO-d₆): δ=1.25, 1.40 and 1.46 (d, s, and s, 18H); 2.95 (s, br,3H); 4.05 (tr, 1H); 5.10 (d, 1H); 7.05(s, 1H) ppm

EXAMPLE 8H2R-[2α,3α(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, 1-methylhydrazide, potassium salt

[2R-[2α,3α(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, 2-[(1,1-dimethylethoxy)carbonyl]-1-methylhydrazide, potassium salt(1.10 g, 1.83 mmole) was added to 45 ml of trifluoroacetic acid at 0° C.and the solution was stirred at this temperature for 3 hours. Thevolatiles were evaporated in vacuo and the resulting oily residue wascrystallized from ether. Filtration and drying in vacuo yielded thetitle compound as a colorless crystalline solid, 1.34 g, m.p. 225° C.

IR(KBr): 1760(s) cm⁻¹ β-lactam carbonyl

¹ H-NMR(100MHz, DMSO-d₆ /TFA-d): δ=1.25(d, 3H); 1.60 (d, 6H); 3.35(s,3H); 4.05(tr, 1H); 5.07(q, 1H); 7.05(s, 1H) ppm

EXAMPLE 8I[2R-[2α,3α(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, 2-(3,4-dihydroxy-5-sulfobenzoyl)-1-methylhydrazide, dipotassiumsalt

A solution of 3,4-dihydroxy-5-sulfobenzoic acid (2.02 g, 10 mmole) in 40ml of dimethylformamide at 0° C. is treated with triethylamine (1.01 g,mmole), N-hydroxybenzotriazole monohydrate (1.53 g, 10 mmole) anddicyclohexylcarbodiimide (2.06 g, 10 mmole). The mixture is stirred at0° C. for 1 hour, then is treated with a solution ofR-[2α,3α(Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, 1-methylhydrazide (4.62 g, 10 mmole) and triethylamine (1.01 g, 10mmole) in 20 ml of dimethylformamide. The pH is raised to 8 with theaddition of triethylamine. The resulting mixture is stirred at 20° C.overnight and filtered, and the filtrate is evaporated in vacuo. Theresidue is taken up in water and passed through a pad of ion-exchangeresin (DOWEX AG-50, K+form). The eluate is lyophilized and the solid ischromatographed on HP20 resin to give the title compound.

EXAMPLE 92S-[2α,3α(Z,S)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy-2-methylpropanoicacid, 2-(2,3-dihydroxy-5-sulfobenzoyl)2-methylhydrazide, disodium saltEXAMPLE 9A 1-[(1,1-Dimethylethoxy)carbonyl-1-methylhydrazine

A solution of methylhydrazine (2.3 g, 50 mmole) in 100 ml oftetrahydrofuran and 100 ml of water was treated with BOC anhydride(10.91 g, 50 mmole) at 20° C. and the pH was maintained at 8-9 with thedropwise addition of 2N sodium hydroxide. After the pH stabilized, thesolution was stirred overnight at 20° C. and pH 8-9. The organic solventwas evaporated in vacuo and the residue was extracted with ethylacetate. The organic solution was washed with water, dried over sodiumsulfate and evaporated. The residual oil was flash-distilled in vacuo togive 3.68 g of the title compound as a colorless oil.

IR(film): 1695 cm⁻¹

¹ H-NMR(DMSO-d6): δ=1.40(s, 9H); 2.90(s, 3H); 4.47(s, 2H) ppm

EXAMPLE 9B

[2S-[2α,3α(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)-amino]-2-oxoethylidene]amino]oxy-2-methylpropanoicacid, 2-[(1,1-dimethylethoxy)carbonyl-2-methylhydrazide, potassium salt

A solution of[2S-[2α,3α(Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino-2-oxoethylidene]amino]oxy-2-methylpropanoicacid (2.18 g, 5.0 mmole) in 50 ml of dimethylformamide at 20° C. wastreated with tri-n-butylamine (0.93 g, 5.0 mmole),N-hydroxybenzotriazole hydrate (0.80 g, 5.0 mmole),4-(N,N-dimethylamino)-pyridine (60 mg, 0.5 mmole) anddicyclohexylcarbodiimide (1.13 g, 5.5 mmole). After stirring for 30minutes 1-[(1,1-dimethylethoxy)carbonyl]-1-methylhydrazine (0.73 g, 5.0mmole) was added and stirring was continued for 3 days. The mixture wasfiltered and the filtrate was evaporated in vacuo. The residue wasdissolved in 20 ml of acetone and the solution was treated withpotassium perfluorobutanesulfonate (1.70 g, 5.0 mmole). The resultingslurry was diluted with ether and filtered. The solid was purified onXAD-2* resin with a water-acetonitrile gradient to give the titlecompound as a white lyophilate, 390 mg.

IR(KBr): 1760 cm⁻¹ (β-lactam carbonyl)

¹ H-NMR(DMSO-d₆): δ=1.30-1.55(m, 18H); 2.91(s, 3H); 3.70(q, 1H); 4.55(dof d, 1H); 6.80(s, 1H); 7.29(s, br,2H); 9.22(d, 1H); 9.65(s, 1H)ppm

EXAMPLE 9C[2S-[2α,3β(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, 2-methylhydrazide, potassium salt

[2S-[2α,3β(Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]--oxoethylidene]amino]oxy]-2-methylpropanoicacid, 2-[(1,1-dimethylethoxy)carbonyl]-2-methylhydrazide, potassium salt(1.10 g, 1.83 mmole) is added to 45 ml of trifluoroacetic acid at 0° C.and the solution is stirred at this temperature for 3 hours. Thevolatiles are evaporated in vacuo and the resulting oily residue iscrystallized from ether. Filtration and drying in vacuo yields the titlecompound.

EXAMPLE 9D [2S-[2α,3β(Z,S)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, 2-(2,3-dihydroxy-5-sulfobenzoyl)-2-methylhydrazide, disodium salt

A solution of 2,3-dihydroxy-5-sulfobenzoic acid (2.02 g, 10 mmole) in 40ml of dimethylformamide at 0° C. is treated with triethylamine (1.01 g,10 mmole), N-hydroxybenzotriazole monohydrate (1.53 g, 10 mmole) anddicyclohexylcarbodiimide (2.06 g, 10 mmole). The mixture is stirred at0° C. for 1 hour, then is treated with a solution of[2S-[2α,3β(Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, 2-methylhydrazide, potassium salt (4.62 g, 10 mmole) andtriethylamine (1.01 g, 10 mmole, plus enough amine to give a pH 8solution) in 20 ml of dimethylformamide. The resulting mixture isstirred at 20° C. overnight and filtered, and the filtrate is evaporatedin vacuo. The residue is taken up in water and passed through a pad ofion-exchange resin (DOWEX AG-50, Na+ form). The eluate is lyophilizedand the solid is chromatographed on HP-20 resin to give the titlecompound.

EXAMPLE 10[2S-[2α,3β(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, 2-(3,4-dihydroxy-5-sulfobenzoyl)-1,2-dimethylhydrazide,dipotassium salt EXAMPLE 10A[2S-[2α,3β(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, 1,2-dimethylhydrazide, potassium salt

A solution of[2S-[2α,3β(Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, (1.3 g, 3.0 mmole) in 20 ml of dimethylformamide at 0° C wastreated with tri-n-butylamine (0.55 g, 3.0 mmole),N-hydroxybenzotriazole hydrate (0.4 g, 3.0 mmole),4-(N,N-dimethylamino)pyridine (40 mg, 0.3 mmole), anddicyclohexylcarbodiimide (0.68 g, 3.3 mmole). After stirring at 0° C.for 1 hour, the mixture was treated dropwise with a solution of1,2-dimethylhydrazine dihydrochloride (0.4 g, 3.0 mmole) andtri-n-butylamine (1.1 g, 6.0 mmole) in 20 ml of dimethylformamide. Themixture was stirred for 2 days at 20° C. and the resulting slurry wasfiltered. The filtrate was evaporated in vacuo, the residue dissolved,in water, and the pH adjusted to 6.5 with potassium bicarbonatesolution. An equal volume of acetonitrile was added, the mixturefiltered, and the filtrate stirred with DOWEX 50 W ×8 (K+) ion exchangeresin. The mixture was filtered and the product solution waslyophilized. The residue was chromatographed on XAD resin in awater-acetonitrile gradient, and then on Organogen using water aseluent, giving the title compound as 0.36 g of a colorless lyophilate,245°-255° C.

IR(KBr): 1760 cm⁻¹ β-lactam carbonyl

¹ H-NMR(DMSO-d₆): δ=1.40(d, 3H); 1.55(s, 6H); 2.70(s, 3H); 3.35(s, 3H);3.75(m, 1H); 4.50(d, 1H); 7.08(s, 1H) ppm

EXAMPLE 10B[2S-[2α,3β(Z)]]-2-[[[1-(2-Amino-4-thiazolyl)-2-[(2-methyl-4-oxo-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, 2-(3,4-dihydroxy-5-sulfobenzoyl)-1,2-dimethylhydrazide dipotassiumsalt

A solution of 3,4-dihydroxy-5-sulfobenzoic acid (2.02 g, 10 mmole) in 40ml of dimethylformamide at 0° C. is treated with triethylamine (1.01 g,10 mmole), N-hydroxybenzotriazole monohydrate (1.53 g, 10 mmole) anddicyclohexylcarbodiimide (2.06 g, 10 mmole). The mixture is stirred at0° C. for 1 hour, then is treated with a solution of[2S-[2α,3β(Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, 1,2-dimethylhydrazide, potassium salt (4.62 g, 10 mmole) andtriethylamine (1.01 g, 10 mmole, plus enough amine to give a pH 8solution) in 20 ml of dimethylformamide. The resulting mixture isstirred at 20° C. overnight and filtered, and the filtrate is evaporatedin vacuo. The residue is taken up in water and passed through a pad ofion-exchange resin (DOWEX AG-50, K+ form). The eluate is lyophilized andthe solid is chromatographed on HP-20 resin to give the title compound.

What we claim is:
 1. A compound of the formula ##STR34## andpharmaceutically acceptable salts thereof, wherein R₃ and R₄ are thesame or different and each is hydrogen or alkyl or R₃ and R₄ takentogether with the nitrogen atoms to which they are attached form a1,2-diazacyclobutane, 1,2-diazacyclopentane, 1,2-diazacyclohexane, or1,2-diazacycloheptane ring and Y₁ and Y₂ are either hydrogen or hydroxybut are not the same.
 2. A compound according to claim 1,3,4-dihydroxy-5-sulfobenzoic acid hydrazide.
 3. A compound according toclaim 1, 2,3-dihydroxy-5-sulfobenzoic acid hydrazide.